Diabetes is extraordinarily prevalent in older adults, the most rapidly growing yet vulnerable portion of the US population, and it dramatically increases the risks of cardiovascular disease (CVD) and congestive heart failure (CHF) in this age group. Despite marked effects of aging on fat mass and distribution, little is known about the pathways that lead to diabetes and the mechanisms by which diabetes leads to CVD in older adults. Emerging evidence implicates two key candidate pathways in diabetes and CVD - the adipocyte-hepatocyte axis in the development of diabetes, and the advanced glycation endproduct (AGE)-profibrosis pathway in CVD complications. Few population-based cohort studies have sufficient numbers of participants, duration, stored specimens, measures of comorbidity, and confirmed outcomes to comprehensively examine these pathways in older adults. We propose an integrated, multi-institutional evaluation of determinants and consequences of diabetes in older adults, using a well-defined, large, and carefully followed cohort of 5,888 older men and women - the Cardiovascular Health Study (CHS). CHS has over 15 years of adjudicated follow-up, including repeated clinic visits with measures of anthropometrics, medication use, subclinical vascular disease, blood and urine biomarkers, and systematic ascertainment of CVD events. We propose to use this rich resource to examine prospectively (1) the associations of adipocyte- and liver-derived products (total and high-molecular-weight adiponectin, fatty-acid binding protein 4, free fatty acids, and fetuin-A) with incident diabetes, (2) the concomitant and potentially divergent associations of these markers with CVD, and (3) the associations of advanced glycation end-products and profibrotic markers (transforming growth factor 2, procollagen III N-terminal peptide) with microvascular and clinical CVD. CHS, with over 350 individuals with incident diabetes, over 725 with prevalent diabetes, nearly 1,300 cases of CVD, and over 2,500 deaths, provides a unique opportunity for our interdisciplinary team of new investigators to evaluate the associations of these candidate pathways with the risks of diabetes and CVD with power, methodological rigor, and cost and specimen efficiency. The findings will advance scientific knowledge and direct future research on diabetes and CVD in older adults, and may lead to novel strategies for prevention and treatment of these disorders that have reached epidemic proportions in elders. PUBLIC HEALTH RELEVANCE: Diabetes is particularly common among older persons; the most rapidly growing segment of the population. Older persons are at highest risk of cardiovascular disease, and diabetes is a major contributing factor. However, our understanding of the determinants and cardiovascular consequences of diabetes in older persons is incomplete, as this age-group is substantially understudied in prior research. The results of this integrated research will provide novel insights to the pathogenesis and cardiovascular consequences of diabetes in older persons, and will inform new avenues for prevention and treatment in this vulnerable and growing population.